The invention relates to a stereospecific method for the preparation of 2(S),4(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-aryloctanoyl amides in the form of 5(R)- or 5(S)-diastereomers and mixtures thereof, as well as their physiologically acceptable salts; and new compounds used in the multistage process as intermediates.
In EP-A-0 678 503, xcex4-amino-xcex3-hydroxy-xcfx89-aryl-alkanecarboxamides are described, which exhibit renin-inhibiting properties and could be used as antihypertensive agents in pharmaceutical preparations. The manufacturing procedures described are unsatisfactory in terms of the number of process steps and yields and are not suitable for an industrial process. A disadvantage of these processes is also that the total yields of pure diastereomers that are obtainable are too small.
D. A. Sandham et al. describe in Tetrahedron Letters, Volume 41, Issue 51, pages 10085-10089 (2000), a synthesis for the preparation of 2(S),4(S),5(S),7(S)-2-isopropyl-4-hydroxy-5-amino-7-isopropyl-8-[(3-methoxy-n-propoxy)-4-methoxyphenyl]octanoyl amide, in which a Grignard compound of 1-[(3-methoxy-n-propoxy)-4-methoxyphenyl]-2-isopropyl-3-chloropropane is reacted with a pseudoephedrine-protected isopropylvalerolactone aldehyde, followed by hydrolysis, to form a compound of formula A 
The compound of formula A is obtained in a yield of only 51%, the R:S ratio, in relation to the OH group, being 85:15. The OH group is then converted to a leaving group (brosylate). The reaction with sodum azide yields the corresponding azido compound which with 3-amino-2,2-dimethylpropionamide on opening of the lactone ring gives the corresponding amide. Catalytic hydrogenation then yields the desired amine.
It has now been surprisingly found that these alkanecarboxamides are obtainable both in high total yields and in a high degree of purity when the amino group is introduced with Grignard coupling. According to this process step, customary purification and separation procedures can if necessary be used for the preparation of pure diastereomers. The process is suitable for industrial scale manufacture.
A first object of the invention is a process for the preparation of compounds of formula I and their physiologically acceptable salts, 
wherein
R1 and R2 are, independently of one another, H, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy, C1-C6alkoxy-C1-C6alkyl, or C1-C6alkoxy-C1-C6alkyloxy, R3 is C1-C6alkyl, R4 is C1-C6alkyl, and R5 is C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy-C1-C6-alkyl, C1-C6alkanoyloxy-C1-C6alkyl, C1-C6aminoalkyl, C1-C6alkylamino-C1-C6-alkyl, C1-C6-dialkylamino-C1-C6-alkyl, C1-C6-alkanoylamido-C1-C6-alkyl, HO(O)Cxe2x80x94C1-C6-alkyl, C1-C6alkyl-Oxe2x80x94(O)Cxe2x80x94C1-C6alkyl, H2Nxe2x80x94C(O)xe2x80x94C1-C6alkyl, C1-C6alkyl-HNxe2x80x94C(O)xe2x80x94C1-C6alkyl or (C1-C6alkyl)2Nxe2x80x94C(O)xe2x80x94C1-C6-alkyl, comprising the steps
a) reaction of a compound of formula II, 
wherein R4 is as defined above, with a hydroxylamine of formula ZNHOH (III), wherein Z is a removable protecting group, to form a compound of formula IV, 
b) reaction of a compound of formula IV with a metal organic derivative of a compound of formula V, 
wherein R1, R2 and R3 are as defined above, and Y is Cl, Br or I, to form a compound of formula VI, 
c) removal of the hydroxyl group to form a compound of formula VII, 
d) removal of the pseudoephedrine protecting group to form compounds of formula VIII, 
or the performance of step d) before step c), or the performance of steps c) and d) together in one reaction vessel,
e) reaction of a compound of formula VIII with an amine of formula R5xe2x80x94NH2 to form a compound of formula IX 
f) removal of protecting group Z for the preparation of compounds of formula I.
With the process according to the invention, preferably the 5(S)-diastereomer of formula Ia 
As an alkyl, R1 and R2 may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl.
As a halogenalkyl, R1 and R2 may be linear or branched and preferably comprise 1 to 4 C atoms, especially 1 or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.
As an alkoxy, R1 and R2 may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methoxy, ethoxy, n- and i-propyloxy, n-, i- and t-butyloxy, pentyloxy and hexyloxy.
As an alkoxyalkyl, R1 and R2 may be linear or branched. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyl group preferably comprises 1 to 4 C atoms. Examples are methoxymethyl, 1-methoxyeth-2-yl, 1-methoxyprop-3-yl, 1-methoxybut-4-yl, methoxypentyl, methoxyhexyl, ethoxymethyl, 1-ethoxyeth-2-yl, 1-ethoxyprop-3-yl, 1-ethoxybut-4-yl, ethoxypentyl, ethoxyhexyl, propyloxymethyl, butyloxymethyl, 1-propyloxyeth-2-yl and 1-butyloxyeth-2-yl.
As a C1-C6alkoxy-C1-C6alkyloxy, R1 and R2 may be linear or branched. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyloxy group preferably comprises 1 to 4 C atoms. Examples are methoxymethyloxy, 1-methoxyeth-2-yloxy, 1-methoxyprop-3-yloxy, 1-methoxybut-4-yloxy, methoxypentyloxy, methoxyhexyloxy, ethoxymethyloxy, 1-ethoxyeth-2-yloxy, 1-ethoxyprop-3-yloxy, 1-ethoxybut-4-yloxy, ethoxypentyloxy, ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 1-propyloxyeth-2-yloxy and 1-butyloxyeth-2-yloxy.
In a preferred embodiment, R1 is methoxy- or ethoxy-C1-C4alkyloxy, and R2 is preferably methoxy or ethoxy. Particularly preferred are compounds of formula I, wherein R1 is 1-methoxyprop-3-yloxy and R2 is methoxy.
As an alkyl, R3 and R4 may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl. In a preferred embodiment, R3 and R4 in compounds of formula I are in each case isopropyl.
As an alkyl, R5 may be linear or branched and preferably comprise 1 to 4 C atoms. Examples of alkyl are listed hereinabove. Methyl, ethyl, n- and i-propyl, n-, i- and t-butyl are preferred.
As a C1-C6hydroxyalkyl, R5 may be linear or branched and preferably comprise 2 to 6 C atoms. Some examples are 2-hydroxyethy-1-yl, 2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl, 2-, 3- or 4-hydroxybut-1-yl, hydroxypentyl and hydroxyhexyl.
As a C1-C6alkoxy-C1-C6alkyl, R5 may be linear or branched. The alkoxy group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are 2-methoxyethy-1-yl, 2-methoxyprop-1-yl, 3-methoxyprop-1-yl, 2-, 3- or 4-methoxybut-1-yl, 2-ethoxyethy-1-yl, 2-ethoxyprop-1-yl, 3-ethoxyprop-1-yl, and 2-, 3- or 4-ethoxybut-1-yl.
As a C1-C6alkanoyloxy-C1-C6alkyl, R5 may be linear or branched. The alkanoyl group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are formyloxymethyl, formyloxyethyl, acetyloxyethyl, propionyloxyethyl and butyroyloxyethyl.
As a C1-C6aminoalkyl, R5 may be linear or branched and preferably comprise 2 to 4 C atoms. Some examples are 2-aminoethyl, 2- or 3-aminoprop-1-yl and 2-, 3- or 4-aminobut-1-yl.
As a C1-C6alkylamino-C1-C6alkyl and C1-C6dialkylamino-C1-C6-alkyl, R5 may be linear or branched. The alkylamino group preferably comprises C1-C4alkyl groups and the alkyl group preferably 2 to 4 C atoms. Some examples are 2-methylaminoeth-1-yl, 2-dimethylaminoeth-1-yl, 2-ethylaminoeth-1-yl, 2-ethylaminoeth-1-yl, 3-methylaminoprop-1-yl, 3-dimethylaminoprop-1-yl, 4-methylaminobut-1-yl and 4-dimethylaminobut-1-yl.
As a C1-C6alkanoylamido-C1-C6alkyl, R5 may be linear or branched. The alkanoyl group preferably comprises 1 to 4 C atoms and the alkyl group preferably 1 to 4 C atoms. Some examples are 2-formamidoeth-1-yl, 2-acetamidoeth-1-yl, 3-propionylamidoeth-1-yl and 4-butyroylamidoeth-1-yl.
As a HO(O)Cxe2x80x94C1-C6alkyl, R5 may be linear or branched, and the alkyl group preferably comprises 2 to 4 C atoms. Some examples are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.
As a C1-C6-alkylxe2x80x94Oxe2x80x94(O)Cxe2x80x94C1-C6alkyl, R5 may be linear or branched, and the alkyl groups preferably comprise independently of one another 1 to 4 C atoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonyleth-1-yl, 3-methoxycarbonylprop-1-yl, 4-methoxycarbonylbut-1-yl, ethoxycarbonylmethyl, 2-ethoxycarbonyleth-1-yl, 3-ethoxycarbonylprop-1-yl, and 4-ethoxycarbonylbut-1-yl.
As a H2Nxe2x80x94C(O)xe2x80x94C1-C6alkyl, R5 may be linear or branched, and the alkyl group preferably comprises 2 to 6 C atoms. Some examples are carbamidomethyl, 2-carbamidoeth-1-yl, 2-carbamido-2,2-dimethyleth-1-yl, 2- or 3-carbamidoprop-1-yl, 2-, 3- or 4-carbamidobut-1-yl, 3-carbamido-2-methylprop-1-yl, 3-carbamido-1,2-dimethylprop-1-yl, 3-carbamido-3-methylprop-1-yl, 3-carbamido-2,2-dimethylprop-1-yl, 2-, 3-, 4- or 5-carbamidopent-1-yl, 4-carbamido-3,3- or -2,2-dimethylbut-1-yl.
As a C1-C6alkyl-HNxe2x80x94C(O)xe2x80x94C1-C6-alkyl or (C1-C6alkyl)2Nxe2x80x94C(O)xe2x80x94C1-C6-alkyl, R5 may be linear or branched, and the NH-alkyl group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 6 C atoms. Examples are the carbamidoalkyl groups defined hereinabove, whose N atom is substituted with one or two methyl, ethyl, propyl or butyl.
A preferred subgroup of compounds of formula I is that in which R1 is C1-C4alkoxy or C1-C4alkoxy-C1-C4alkyloxy, R2 is C1-C4alkoxy, R3 is C1-C4alkyl, R4 is C1-C4alkyl and R5 is H2NC(O)xe2x80x94C1-C6alkyl which if necessary is N-monosubstituted or N-di-C1-C4alkyl substituted.
A more preferred subgroup of compounds of formula I is that in which R1 is methoxy-C2-C4-alkyloxy, R2 is methoxy or ethoxy, R3 is C2-C4alkyl, R4 is C2-C4alkyl and R5 is H2NC(O)xe2x80x94C1-C6alkyl.
An especially preferred compound of formula I is that in which R1 is 3-methoxy-prop-3-yloxy, R2 is methoxy, R3 and R4 are 1-methyleth-1-yl, and R5 is H2NC(O)xe2x80x94[C(CH3)2]xe2x80x94CH2xe2x80x94.
Protecting groups Z in compounds of formula III are generally known. Preferred groups are those which can be removed by hydrogenation, such as silyl groups and preferably mono-, di- or triarylmethyl, special preference being for mono-, di- or triphenylmethyl. The aryl groups may be unsubstituted or substituted for example with halogen, C1-C4alkyl, C1-C4alkoxy or C1-C4halogenalkyl. Some examples are naphthylmethyl, methyl- or dimethylbenzyl, methoxy- or dimethoxybenzyl, chlorobenzyl, trifluoromethylbenzyl, benzyl, diphenylmethyl, di(methylphenyl)methyl, di(methoxyphenyl)methyl, trityl, tri(methylphenyl)methyl, tri(methoxyphenyl)methyl, trimethylsilyl, triphenylsilyl and methyldiphenylsilyl. Benzyl is especially preferred.
The individual process steps may be carried out in the presence of solvent. Suitable solvents are water and organic solvents, especially polar organic solvents, which can also be used as mixtures of at least two solvents. Examples of solvents are hydrocarbons (petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene, xylene), halogenated hydrocarbon (methylene chloride, chloroform, tetrachloroethane, chlorobenzene); ether (diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl or diethyl ether); carbonic ester and lactone (methyl acetate, ethyl acetate, methyl propionate, valerolactone); N,N-substituted carboxamides and lactams (dimethylformamide, dimethylacetamide, N-methylpyrrolidone); ketones (acetone, methylisobutylketone, cyclohexanone); sulfoxides and sulfones (dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone); alcohols (methanol, ethanol, n- or i-propanol, n-, i- or t-butanol, pentanol, hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl or dihydroxymethyl cyclohexane, benzyl alcohol, ethylene glycol, diethylene glycol, propanediol, butanediol, ethylene glycol monomethyl or monoethyl ether, and diethylene glycol monomethyl or monoethyl ether; nitriles (acetonitrile, propionitrile); tertiary amines (trimethyl-, triethyl-, tripropyl- and tributylamine, pyridine, N-methylpyrrolidine, N-methylpiperazine, N-methylmorpholine) and organic acids (acetic acid, formic acid).
Process Step a)
Compounds of formula II are known, and their preparation is described by D. A. Sandham et al. in Tetrahedron Letters, Volume 41, Issue 51, pages 10090ff (2000). The compounds of formula II are unstable. It is therefore recommended that the aldehyde be prepared immediately before the reaction with a hydroxylamine. To this end, the corresponding alcohol is oxidized to the aldehyde for example with a complex of pyridine and sulfur trioxide, and the aldehyde then extracted from the reaction mixture. Before further use, the solvent may be partially removed for concentration.
The reaction with a compound of formula III may be carried out at temperatures of xe2x88x9220 to 100xc2x0 C. and preferably at 0 to 50xc2x0 C. The reaction is expediently carried out in an organic solvent, preferably in halogenated hydrocarbons, for example methylene chloride, chloroform, 1,2-dichloroethane or tetrachloroethane. To bind the reaction water, it is advantageous to add a water-binding agent, for example anhydrous metal salts, such as sodium sulfate or calcium chloride, or silica gels. The hydroxylamine is added in at least equimolar quantities or in slight excess. The isolation may be carried out in a known manner, for example by evaporation of the solvent, filtration of the residue and crystallization or chromatographic separation of the filtrate. The compounds of formula IV are formed in high yields of up to 90% or more.
Process Step b)
Metal organic derivatives of a compound of formula V are for example those of formula X, 
wherein Y1 is an alkali metal (lithium, sodium and potassium) or xe2x80x94MeY, wherein Y is Cl, Br or iodine and Me is Mg, Zn, Hg or Cd. Preferred compounds are those wherein Y1 is MgY. The preparation of metal organic derivatives from compounds of formula V is known and described in more detail in the example. The reaction is preferably carried out in ethers or aromatic hydrocarbons as solvents. Some examples are diethylether, dipropylether, dibutylether, methylpropylether, methylbutylether, tetrahydrofuran and dioxane, as well as benzene, toluene and xylene. The reaction temperature may be xe2x88x9270 to 100 and preferably xe2x88x9230 to 50xc2x0 C. The compounds of formula IV and the metal organic derivatives of compounds of formula V can be used in equimolar quantities, or an excess of the compounds of said metal organic derivatives are used. One may proceed in such a way that first the said metal organic derivatives are prepared and these added without isolation to a solution of a compound of formula IV. The ratio of 5(S):5(R)-diastereomer is about 30:70. This ratio may be reversed and essentially increased for example to 70:30 or higher if the reaction is carried out in the presence of heavy metal salts, or if the said metal organic derivatives are transmetallated with heavy metal salts (see D. A. Sandham et al. in Tetrahedron Letters, Volume 41, Issue 51, pages 10090ff (2000)). Suitable metal salts are those from the group of lanthanides and the first and eighth subgroup of the periodic system of elements, for example Cu, Fe, Ni and preferably Ce. Especially suitable are the chlorides or sulfates of these metals. The compounds of formula VI may be isolated in the customary manner by extraction and removal of the solvent. Purification may be performed by distillation or chromatography. The pure 5(S)-diastereomer may be obtained by salt formation with chiral acids; or acylation with chiral acid derivatives and recrystallization or chromatography; or directly by chromatography on chiral columns. The yield may be as high as 80% or more.
Process Step c)
The removal of the hydroxyl group is expediently carried out by means of reduction, preferably in an aqueous-acidic medium. As reduction agent, hydrogen is preferred. This may be advantageously generated as nascent hydrogen by the addition of metals such as zinc or iron to the aqueous-acidic medium. Suitable acids are organic or inorganic acids, such as acetic acid, hydrochloric acid or sulfuric acid. The presence of heavy metal salts such as copper diacetate may be advantageous. The reaction temperature may be 0 to 80xc2x0 C.
Process Step d)
The removal of the pseudoephedrine protecting group may be carried out in aqueous-acidic medium. Suitable acids are organic or inorganic acids, such as acetic acid, hydrochloric acid or sulfuric acid. The reaction temperature may be 0 to 80xc2x0 C. In the context of the invention, process step d) may be carried out before process step c). It has proved advantageous to carry out process steps c) and d) at the same time in one reaction vessel. To this end, a copper salt and zinc powder may for example be placed in an aqueous acid such as acetic acid, followed by the addition of a solution of a compound of formula VI in aqueous acid. In this way, a compound of formula VII is obtainable directly from a compound of formula VI. The compound of formula VIII may be isolated by extraction. Purification may then be carried out by distillation or chromatography. The compound of formula VIII is obtained with a yield of more than 40% using the non-optimized process.
Process Step e)
The reaction of compounds of formula VIII with a compound R5NH2 on opening of the lactone ring to form compounds of formula IX is expediently carried out in the presence of alcohols or amines which are capable of forming activated carbonic esters or carboxamides. Such compounds are well-known. They may be 2-hydroxypyridine, N-hydroxycarboxamides and imides, and carboximides (N-hydroxysuccinimide). The solvents used are organic solvents, tertiary amines being of advantage, for example trimethylamine or triethylamine. The reaction temperature may range for example from approximately 40xc2x0 C. to 150xc2x0 C. and preferably from 50xc2x0 C. to 120xc2x0 C.
Process Step f)
The removal of protecting group Z is expediently carried out catalytically by hydrogenation in the presence of homogeneous or heterogeneous precious metal catalysts or Raney-Nickel. Homogeneous precious metal catalysts (Wilkinson catalysts) are soluble metal complexes of, for example, platinum, palladium, iridium, rhodium and ruthenium, which are known and have been described in the literature. Heterogeneous precious metal catalysts may for example be selected from the metals platinum, palladium, iridium, rhodium and ruthenium on, if necessary, solid carrier materials such as carbon, metal oxides or salts (aluminium oxide), quartz or silica gels. Organic solvents such as alcohols (methanol, ethanol) may advantageously be used as solvents. The reaction temperature may range for example from approximately 0xc2x0 C. to 200xc2x0 C. and preferably from 10xc2x0 C. to 100xc2x0 C. Hydrogenation may be carried out at normal pressure or increased pressure up to 100 bar, for example, and preferably up to 50 bar. It is further expedient to carry out the reaction in the presence of an organic amine (such as ethanolamine) in up to equimolar quantities or in slight excess. The yields are high and may be as much as 90% or more.
The compounds of formula I may be converted to addition salts in a manner known per se by treatment with monobasic or polybasic, inorganic or organic acids. Hemifumarates are preferred.
Also an object of the invention are compounds of formula IV, 
wherein R4 and Z are as defined above, including the preferences.
A further object of the invention are compounds of formula XI in the form of 5(S)- or 5(R)-diastereomers or mixtures thereof, 
wherein R1, R2, R3, R4 and Z are as defined above, including the preferences, and X2 is H or OH.
A further object of the invention are compounds of formula XII in the form of 5(S)- or 5(R)-diastereomers or mixtures thereof, 
wherein R1, R2, R3, R4 and Z are as defined above, including the preferences, and X2 is H or OH.
A further object of the invention are compounds of formula XIII in the form of 5(S)- or 5(R)-diastereomers or mixtures thereof, 
wherein R1, R2, R3, R4, R5 and Z are as defined above, including the preferences.
With the choice of compounds of formula IV, the compounds of formula 1, which per se are complex compounds, can be prepared in a convergent and simple manner, which is especially true of this enantioselective or diastereoselective synthesis. The total yield from all process steps may amount to 40% or more, which makes an industrial application feasible.